C(alkyl)–C(vinyl) bond cleavage enabled by Retro-Pallada-Diels-Alder reaction

Activation and cleavage of carbon–carbon (C–C) bonds is a fundamental transformation in organic chemistry while inert C–C bonds cleavage remains a long-standing challenge. Retro-Diels-Alder (retro-DA) reaction is a well-known and important tool for C–C bonds cleavage but less been explored in methodology by contrast to other strategies. Herein, we report a selective C(alkyl)–C(vinyl) bond cleavage strategy realized through the transient directing group mediated retro-Diels-Alder reaction of a six-membered palladacycle, which is obtained from an in situ generated hydrazone and palladium hydride species. This unprecedented strategy exhibits good tolerances and thus offers new opportunities for late-stage modifications of complex molecules. DFT calculations revealed that an intriguing retro-Pd(IV)-Diels-Alder process is possibly involved in the catalytic cycle, thus bridging both Retro-Diels-Alder reaction and C–C bond cleavage. We anticipate that this strategy should prove instrumental for potential applications to achieve the modification of functional organic skeletons in synthetic chemistry and other fields involving in molecular editing.


REVIEWER COMMENTS
Reviewer #1 (Remarks to the Author): The manuscript of "C(alkyl)-C(vinyl) Bond Cleavage Enabled by Retro-Pallada-Diels-Alder Reaction" by Guan and co-workers is conceptually interesting. It is well known that selective cleavage of C-C bonds is a fundamental transformation in chemical synthesis. In the past several years, excellent works on this topic have been developed. However, the vast majority of the reported works are based on just several fundamental strategies, such as oxidative addition, β-carbon elimination, retroallylation and decarboxylation, new strategy for cleavage of inert C-C bonds is still very rare and remains highly desirable.
In this manuscript, the authors report that α-allyl ketimines undergo a C-C bond cleavage reaction by palladium catalysis through an unprecedented retro-Pd-DA mechanism. Under the standard conditions, a series of substrates in Table 2 and Table 3 were tolerated to afford the corresponding C(alkyl)-C(vinyl) bonds cleavage products in good to high yields. The control experiments in Scheme 2 have confirmed the proposed retro-Pd-DA mechanism. They have also done a detailed DFT calculations to gain insight into the exact mechanism of the reaction. The DFT calculations was a high quality study and proved that the Pd(IV) cyclization-retro-Pd(IV)-DA ( Figure 1A, path III) was the much reasonable process. Notably, when oxygen was instead by hydrogen peroxide, the desired product 2a was obtained in 79% yield in Scheme 2 Eq. (7). The results of computational chemistry are fully consistent with the experimental results. Thus, the Pd(IV) cyclization-retro-Pd(IV)-DA pathway is fully convinced. Another advance of the paper is of that the role of CO in the reaction (facilitate formation of active palladium hydride species) has been well-reasoned by computational chemistry.
Overall, the results in this manuscript are highly important, the work has been carried out with high technical quality and the paper has significant depth and novelty. I think this is a nice paper that deserves publication in Nature Communications.
The following small problems need attention: 1. In order to facilitate readers to repeat DFT calculation, please show the imaginary frequencies of all transition states in the supporting information.
2. On the page 2, introduction, the second paragraph. The retro D-A reaction has long been a difficult problem and has not been solved. This is because it is inverse thermodynamics. In order to solve this problem, the current method is to make the retro-D-A product form aromaticity, thus decreases the Gibbs free energy of the product (J. Am. Chem. Soc. 2019, 141, 9731-9738, Angew. Chem. Int. Ed. 2017. There is no direct solution to this problem. Therefore, any form of retro D-A reaction is important and challenging. Please amend the description of this point in this paragraph.
Reviewer #3 (Remarks to the Author): This paper described an interesting C-C bond cleavage protocol through retro-pallada-Diels-Alder pathway. The reaction shows promising application prospect in chemical modification of β,γ-vinyl ketones due to its high site-selectivity and good functional group tolerances. The authors have proposed six-membered palladacycle mechanisms, and have investigated the detailed mechanism by control experiments and DFT calculations.
After carefully checking the DFT calculations in the paper, this reviewer finds that the selected computation methods are appropriate and provides reliable theoretical insights for this complex chemical synthetic experiment.
Step-by-step mechanism presented in this paper suggests that the energetically favored path-III, that well interprets the Pd-catalyzed cyclization and ring-opening processes. The promotion effects of CO and O2 in their experiments have been reasonably explained through these computational results.
In my opinion, the elaborate reaction path network proposed in this paper contributes to get deeper understanding of the retro-pallada-DA reactions and offers valuable reference for future experimental explorations. I recommend acceptance after addressing the following minor comments.
1) The zero energy should be addressed in SI. The relative energies and free energies (at 298.15K) with respect to Im1 are in kcal/mol. Figure S1 was relative difference between ΔG of Im-a and TS-a, which is better expressed as ΔΔG. Table S1 is not consistent.

3) Fonts in
These authors reported a palladium-catalyzed reductive cleavage of a C(alkenyl)-C(alkyl) bond. The authors proposed that the beta-carbon elimination reaction takes place via retro-Metala-DA reaction based on the experimental results and theoretical calculations. However, this reviewer is skeptical of their proposed mechanism or working hypothesis of this reaction. Their results shown in equations 5 and 7 can be explained by the following conventional reaction pathway (see the scheme below). Electrophilic palladium(II) species can bind to the alkene moiety of the ketone and then the nucleophilic attack of water generated by a condensation reaction of the ketone with acetohydrazine to the coordinated alkene to give intermediate A in the following scheme. Subsequently, -carbon elimination proceeds to give the corresponding alkyl palladium, oxa--allyl palladium, or palladium enolate complex B. Protonolysis of the palladium with generated HX to give the corresponding ketones and regenerate palladium(II) species.
The reaction mechanism claimed by the authors is speculative, and their results are insufficient to explain their proposed mechanism. Based on the experimental results, they should exclude other possible conventional mechanisms such as those mentioned above.
They described their working hypothesis using metalacyclohexene in Scheme 1A, and their proposed intermediate is a metalateterahyudropyridazine derivative, not a metalacylohexene intermediate. This description needs to be more accurate to understand the novelty of this type of metala-electrocyclic reaction, and they should rationally describe the working hypothesis using a suitable intermediate.
As described above their result described in this manuscript does not satisfy the requirement of Nature Communications.

[Additional comments]
On page 3, line 52 and 53: they should cite references for supporting the contents (2) and (3).

Point-by-point response to the reviewers' comments
To Reviewer 1: The manuscript of "C(alkyl)-C(vinyl) Bond Cleavage Enabled by Retro-Pallada-Diels-Alder Reaction" by Guan and co-workers is conceptually interesting. It is well known that selective cleavage of C-C bonds is a fundamental transformation in chemical synthesis. In the past several years, excellent works on this topic have been developed. However, the vast majority of the reported works are based on just several fundamental strategies, such as oxidative addition, β-carbon elimination, retro-allylation and decarboxylation, new strategy for cleavage of inert C-C bonds is still very rare and remains highly desirable.
In this manuscript, the authors report that α-allyl ketimines undergo a C-C bond cleavage reaction by palladium catalysis through an unprecedented retro-Pd-DA mechanism. Under the standard conditions, a series of substrates in Table 2 and Table 3 were tolerated to afford the corresponding C(alkyl)-C(vinyl) bonds cleavage products in good to high yields. The control experiments in Scheme 2 have confirmed the proposed retro-Pd-DA mechanism. They have also done a detailed DFT calculations to gain insight into the exact mechanism of the reaction.
The DFT calculations was a high quality study and proved that the Pd(IV) cyclization-retro-Pd(IV)-DA ( Figure 1A, path III) was the much reasonable process. Notably, when oxygen was instead by hydrogen peroxide, the desired product 2a was obtained in 79% yield in Scheme 2 Eq. (7). The results of computational chemistry are fully consistent with the experimental results. Thus, the Pd(IV) cyclization-retro-Pd(IV)-DA pathway is fully convinced. Another advance of the paper is of that the role of CO in the reaction (facilitate formation of active palladium hydride species) has been well-reasoned by computational chemistry.
Overall, the results in this manuscript are highly important, the work has been carried out with high technical quality and the paper has significant depth and novelty. I think this is a nice paper that deserves publication in Nature Communications. The following small problems need attention: 1. In order to facilitate readers to repeat DFT calculation, please show the imaginary frequencies of all transition states in the supporting information.
Response: Thanks. The imaginary frequencies have been listed in the revised SI.

2.
On the page 2, introduction, the second paragraph. The retro D-A reaction has long been a difficult problem and has not been solved. This is because it is inverse thermodynamics. In order to solve this problem, the current method is to make the retro-D-A product form aromaticity, thus decreases the Gibbs free energy of the product (J. Am. Chem. Soc. 2019, 141, 9731-9738, Angew. Chem. Int. Ed. 2017. There is no direct solution to this problem. Therefore, any form of retro D-A reaction is important and challenging. Please amend the description of this point in this paragraph.

Response: Thanks. Yes, any form of retro D-A reaction is important and challenging.
Aromaticity process is indeed a promising strategy to enable retro D-A reaction. We have revised our introduction and cited the papers in ref 26 and 27. 3. Some recent papers should be cited: (1) β-Carbon Elimination: Nature Chemistry 2022, 14, 398-406; (2) Oxidative Cleavage: Nature 2022, 610, 81-86.

4.
In abstract, this novel strategy is pioneering research of unprecedented retro-metalla-DA reaction. As a new type of retro-DA reaction, "retro-pallada-Diels-Alder" seems to be better than "retro-pallada-(hetero)DA reaction".

Response:
Thanks. According to reviewer's kind comment, we revised our manuscript.
To the Reviewer 2: 1. These authors reported a palladium-catalyzed reductive cleavage of a C(alkenyl)-C(alkyl) bond.
The authors proposed that the beta-carbon elimination reaction takes place via retro-Metala-DA reaction based on the experimental results and theoretical calculations. However, this reviewer is skeptical of their proposed mechanism or working hypothesis of this reaction. Their results shown in equations 5 and 7 can be explained by the following conventional reaction pathway (see the scheme below). Electrophilic palladium(II) species can bind to the alkene moiety of the ketone and then the nucleophilic attack of water generated by a condensation reaction of the ketone with acetohydrazine to the coordinated alkene to give intermediate A in the following scheme.
Subsequently, beta-carbon elimination proceeds to give the corresponding alkyl palladium, oxa-piallyl palladium, or palladium enolate complex B. Protonolysis of the palladium with generated HX to give the corresponding ketones and regenerate palladium(II) species.
The reaction mechanism claimed by the authors is speculative, and their results are insufficient to explain their proposed mechanism. Based on the experimental results, they should exclude other possible conventional mechanisms such as those mentioned above.

/ 4
Response: Thanks. We understand your concerns but can hardly agree with you.
The reaction pathway raised by reviewer 2 is unreasonable if considering the substrates and conditions in all the sections, including condition optimization, substrate scope screening and control experiments. The reasons are listed as following: (1) According to reviewer's mechanism, substrates without phenyl substitute on alkene group (2) According to reviewer's mechanism, the compound 7 in equations 4 should give the desired product. However, it was not the truth.
(3) As we shown in Table 1 and equations 7, the oxygen played an important role in our reaction.
However, the reviewer proposed mechanism is not related to oxygen.
The mechanism in this manuscript is convinced as it was consistent with all the detailed experiment results including

Response:
Thank you very much.

To the Reviewer 3:
This paper described an interesting C-C bond cleavage protocol through retro-pallada-Diels- Alder pathway. The reaction shows promising application prospect in chemical modification of β,γ-vinyl ketones due to its high site-selectivity and good functional group tolerances. The authors have proposed six-membered palladacycle mechanisms, and have investigated the detailed mechanism by control experiments and DFT calculations.
After carefully checking the DFT calculations in the paper, this reviewer finds that the selected computation methods are appropriate and provides reliable theoretical insights for this complex chemical synthetic experiment.
Step-by-step mechanism presented in this paper suggests that the energetically favored path-III, that well interprets the Pd-catalyzed cyclization and ringopening processes. The promotion effects of CO and O2 in their experiments have been reasonably explained through these computational results.
In my opinion, the elaborate reaction path network proposed in this paper contributes to get deeper understanding of the retro-pallada-DA reactions and offers valuable reference for future experimental explorations. I recommend acceptance after addressing the following minor comments.
1. The zero energy should be addressed in SI. The relative energies and free energies (at 298.15K) with respect to Im1 are in kcal/mol.

Response:
Thanks. The data has been addressed in the revised SI.